Noncovalent Association with Stress Protein Facilitates Cross-Priming of CD8 super(+) T Cells to Tumor Cell Antigens by Dendritic Cells

• Published in: The Journal of immunology (1950) Vol. 168; no. 1; pp. 108 - 117
• Main Authors: Kammerer, R, Stober, D, Riedl, P, Oehninger, C, Schirmbeck, R, Reimann, J
• Format: Journal Article
• Language: English
• Published: 01.01.2002
• Subjects: CD8 antigen; Hsp73 protein
• ISSN: 0022-1767

A viral oncogene carrying well-defined K super(b)/D super(b)-restricted epitopes was expressed in a heat shock protein (hsp)-associated or nonassociated form in the murine tumor cells P815 and Meth-A. Wild-type SV40 large T-Ag (wtT-Ag) is expressed without stable hsp association; mutant (cytoplasmic cT-Ag) or chimeric (cT272-green fluorescent fusion protein) T-Ag is expressed in stable association with the constitutively expressed, cytosolic hsp73 (hsc70) protein. In vitro, remnants from apoptotic wtT-Ag- or cT-Ag-expressing tumor cells are taken up and processed by immature dendritic cells (DC), and the K super(b)/D super(b)-binding epitopes T1, T2/3, and T4 of the T-Ag are cross-presented to CTL in a TAP-independent way. DC pulsed with remnants of transfected, apoptotic tumor cells cross-presented the three T-Ag epitopes more efficiently when they processed ATP-sensitive hsp73/cT-Ag complexes than when they processed hsp-nonassociated (native) T-Ag. In vivo, more IFN- gamma -producing CD8 super(+) T cells were elicited by a DNA vaccine that encoded hsp73-binding mutant T-Ag than by a DNA vaccine that encoded native, non-hsp-binding T-Ag. Three- to 5-fold higher numbers of T-Ag (T1-, T2/3-, or T4-) specific, D super(b)/K super(b)-restricted IFN- gamma -producing CD8 super(+) T cells were primed during the growth of transfected H-2 super(d) Meth-A/cT tumors than during the growth of transfected Meth-A/T tumors in F sub(1)(b x d) hosts. Hence, the association of an oncogene with constitutively expressed, cytosolic hsp73 facilitates cross-priming in vitro and in vivo of CTL by DC that process material from apoptotic cells.